title: Shikonin inhibits thyroid cancer cell growth and invasiveness through targeting major signaling pathways.
abstract: BACKGROUND
  Shikonin, which is an active naphthoquinone isolated from traditional Chinese herbal medicine Zi Cao, has been recently developed to use as an antitumor agent in colorectal cancer, melanoma, leukemia, breast cancer, and hepatocellular cancer. However, its antitumor effect in thyroid cancer remains largely unknown.
  
  
  OBJECTIVE
  The aim of the study was to test the therapeutic potential of shikonin for thyroid cancer and explore the mechanisms underlying antitumor effects of shikonin.
  
  
  METHODS
  We examined the effects of shikonin on proliferation, cell cycle, apoptosis, migration, invasion, and xenograft tumor growth in thyroid cancer cells and the effect of shikonin on proliferation of primary thyroid cancer cells.
  
  
  RESULTS
  Shikonin inhibited thyroid cancer cell proliferation in a dose- and time-dependent manner and induced cell cycle arrest. Moreover, shikonin induced cell apoptosis through reactive oxygen species-mediated DNA damage and activation of the p53 signaling pathway. Our data also showed that shikonin dramatically inhibited thyroid cancer cell migration and invasion by suppressing epithelial-mesenchymal transition and downregulating expression of Slug and MMP-2, -9, and -14. Further elucidation of the mechanisms involved revealed that shikonin markedly repressed the phosphorylation of Erk and Akt and activated the p16/Retinoblastoma protein (Rb) pathway in thyroid cancer cells. Growth of xenograft tumors derived from the thyroid cancer cell line FTC133 in nude mice was significantly inhibited by shikonin. Importantly, we did not find the effect of shikonin on liver function in mice.
  
  
  CONCLUSIONS
  We for the first time demonstrated that shikonin is a potentially effective antitumor agent for thyroid cancers.
authors.affiliation: PhD, Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an 710061, People's Republic of China. phou@mail.xjtu.edu.cn.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.forename: Meiju
authors.initials: M
authors.lastname: Ji
authors.forename: Haixia
authors.initials: H
authors.lastname: Guan
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000819:agonists* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D051379:Mice; D008819:Mice, Nude; D050505:Mutant Proteins / Q000819:agonists / Q000378:metabolism; D009285:Naphthoquinones / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness / Q000517:prevention & control; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050505:Mutant Proteins; D009285:Naphthoquinones; D009363:Neoplasm Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; C016101:shikonin